The long term goal of this project is to understand whether modulating E2 actions in a tissue specific manner could be new strategy to prevent type 2 diabetes (T2DM). T2DM and its vascular complications are the consequences of oxidative stress in tissues. There is a large body of evidence demonstrating that the endogenous estrogen, 17beta-estradiol (E2), protects against T2DM in both rodents and humans in conditions of oxidative stress. Women are naturally protected against T2DM until the age of menopause and then develop insulin resistance and an increased risk of T2DM. This phenomenon is reversed by E2 replacement therapy which also leads to a 35% reduction in the incidence of diabetes in predisposed women. E2 protects female rodents from T2DM by a powerful effect on pancreatic beta-cell function/survival. This effect is reproduced by E2 infusion in male rodents. Our preliminary observations suggest that 1) E2 protects male mice against age-related degradation of insulin secretion and diabetes, 2) E2 protects human pancreatic islets from death induced by oxidative stress and that 3) E2 receptors are cytosolic in pancreatic beta-cells, a localization compatible with anti-apoptotic actions. Our hypothesis is that E2 exhibits potent anti-apoptotic actions which protect pancreatic beta-cells from apoptosis in conditions of oxidative stress. These effects are mediated by E2 receptors (ER) and can be mimicked by selective estrogen receptor modulators (SERM) to prevent and cure diabetes in rodents. To address this issue, we propose: [unreadable] 1) To determine whether the SERM, raloxifene, can prevent pancreatic beta-cell destruction in vivo in diabetic rodents. 2) To demonstrate the importance of the ER-alpha in the protection of pancreatic beta-cells from oxidative stressand destruction using knockout mouse models of E2 deficiency andresistance This project seeks support through the exploratory/developmental grant (R21) mechanism in answer to a specific program announcement (PA-02-008): "pilot and feasibility program in Diabetes, Endocrinology and Metabolism". [unreadable] [unreadable]